Cross-couplings to form carbon-carbon bonds are some of the most utilized reactions for the synthesis of molecules that improve human health. They constitute nearly a quarter of all carbon-carbon bond-forming reactions practiced by process chemists in the pharmaceutical industry. Our long-term objective for this NIH program is to create new transition metal-catalyzed coupling reactions that form the types of carbon-carbon bonds in molecules with medicinal activity. We seek to do so while gaining a quantitative and precise understanding of the mechanisms of these reactions to create a platform for further reaction discovery and to create a framework within which to rationally apply these classes of reactions to synthetic problems. To meet these objectives, we will seek to uncover new transformations with catalysts we discovered previously, to reveal new catalysts that turn notoriously capricious reactions into reliable methods, and to gain precise information about the individual steps of these catalytic processes to build a connection between the structure and properties of the catalytic intermediates and the rates and selectivities of the overall reaction. Our goals for the next grant period are based on published and unpublished findings on 1) new classes of coupling reactions of enolates we discovered that are becoming commonly practiced, 2) new classes of complexes we discovered that mediate the coupling of aryl, vinyl, and allyl electrophiles with enolates, cyanide, trifluoromethyl anions, and main group organometallic reagents with control of absolute stereochemistry in many cases, and 3) new mechanistic information we recently discovered that mandates a reassessment the identity and reactivity of previously proposed intermediates in these and additional commonly practiced coupling and C-H bond functionalization reactions. To achieve these short-term goals we will develop 1) palladium-catalyzed reactions of aryl halides with enolates that currently do not undergo coupling in high yields with broad scope, 2) copper-catalyzed reactions of aryl halides with enolates and sources of trifluoromethyl anions that complement palladium-catalyzed chemistry (and that reduce catalyst cost), 3) palladium-catalyzed coupling reactions, such as the cyanation of aryl halides and carbonylative couplings, that are important for the synthesis of medicinally active compounds but are currently poorly developed or unreliable, 4) coupling of aryl halides with arenes catalyzed by ligandless palladium systems derived from our mechanistic studies, and 5) enantioselective or stereoretentive palladium- and iridium-catalyzed reactions of enolates or hard nucleophiles that form products containing stereogenic quaternary carbons. All of these reactions occur with common nucleophiles and ubiquitous aryl or vinyl halide electrophiles. It is the ability to use these reactions of common reagents for the direct synthesis of key intermediates and pharmacophores from a single, readily available synthetic or commercial intermediate that causes drug candidates to contain the types of carbon-carbon bonds formed by the chemistry of this proposal. PUBLIC HEALTH RELEVANCE: Many of the catalysts and reactions that have resulted from this project dramatically improve methods to prepare pharmaceutical intermediates, and new reactions, new applications of our catalysts, and a mechanistic understanding of these systems that will result from the proposed research promise to be equally important for the synthesis of these and other biologically active materials. Thus, successful development of the proposed research will significantly increase the accessibility of compounds that improve human health.